{"doi":"10.1161/strokeaha.123.042714","title":"Targeting Neutrophil α9 Improves Functional Outcomes After Stroke in Mice With Obesity-Induced Hyperglycemia","abstract":"BACKGROUND: Obesity-induced hyperglycemia is a significant risk factor for stroke. Integrin α9β1 is expressed on neutrophils and stabilizes adhesion to the endothelium via ligands, including Fn-EDA (fibronectin containing extra domain A) and tenascin C. Although myeloid deletion of α9 reduces susceptibility to ischemic stroke, it is unclear whether this is mediated by neutrophil-derived α9. We determined the role of neutrophil-specific α9 in stroke outcomes in a mice model with obesity-induced hyperglycemia. METHODS: α9 Neu-KO (α9 fl/fl MRP8Cre + ) and littermate control α9 WT (α9 fl/fl MRP8Cre − ) mice were fed on a 60% high-fat diet for 20 weeks to induce obesity-induced hyperglycemia. Functional outcomes were evaluated up to 28 days after stroke onset in mice of both sexes using a transient (30 minutes) middle cerebral artery ischemia. Infarct volume (magnetic resonance imaging) and postreperfusion thrombo-inflammation (thrombi, fibrin, neutrophil, phospho-nuclear factor kappa B [p-NFκB], TNF [tumor necrosis factor]-α, and IL [interleukin]-1β levels, markers of neutrophil extracellular traps) were measured post 6 or 48 hours of reperfusion. In addition, functional outcomes (modified Neurological Severity Score, rota-rod, corner, and wire-hanging test) were measured for up to 4 weeks. RESULTS: Stroke upregulated neutrophil α9 expression more in obese mice ( P <0.05 versus lean mice). Irrespective of sex, deletion of neutrophil α9 improved functional outcomes up to 4 weeks, concomitant with reduced infarct, improved cerebral blood flow, decreased postreperfusion thrombo-inflammation, and neutrophil extracellular traps formation (NETosis) ( P <0.05 versus α9 WT obese mice). Obese α9 Neu-KO mice were less susceptible to thrombosis in FeCl 3 injury-induced carotid thrombosis model. Mechanistically, we found that α9/cellular fibronectin axis contributes to NETosis via ERK (extracellular signal-regulated kinase) and PAD4 (peptidyl arginine deiminase 4), and neutrophil α9 worsens stroke outcomes via cellular fibronectin-EDA but not tenascin C. Obese wild-type mice infused with anti–integrin α9 exhibited improved functional outcomes up to 4 weeks ( P <0.05 versus vehicle). CONCLUSIONS: Genetic ablation of neutrophil-specific α9 or pharmacological inhibition improves long-term functional outcomes after stroke in mice with obesity-induced hyperglycemia, most likely by limiting thrombo-inflammation.","journal":"Stroke","year":2023,"id":332407,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9565,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":302411,"name":"Nirav Dhanesha","orcid":"0000-0001-9268-4363","position":1,"is_corresponding":false},{"id":920981,"name":"Brijesh Sutariya","orcid":"0000-0001-8602-0966","position":2,"is_corresponding":false},{"id":302409,"name":"Madankumar Ghatge","orcid":"0000-0002-6606-0108","position":3,"is_corresponding":false},{"id":379233,"name":"Prakash Doddapattar","orcid":"0000-0003-4219-5240","position":4,"is_corresponding":false},{"id":1058562,"name":"Tarun Barbhuyan","orcid":"0000-0002-3878-5806","position":5,"is_corresponding":false},{"id":625796,"name":"Mariia Kumskova","orcid":"0000-0002-2477-3011","position":6,"is_corresponding":false},{"id":625797,"name":"Enrique C. Leira","orcid":"0000-0003-3695-2946","position":7,"is_corresponding":false},{"id":302415,"name":"Anil K. Chauhan","orcid":"0000-0001-8554-0898","position":8,"is_corresponding":false},{"id":625795,"name":"Rakesh B. Patel","orcid":"0000-0001-9727-9738","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-19T01:09:30.139849Z","pmid":"37449422","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}